The novel EZH2 inhibitor tazemetostat has shown clinically meaningful benefit in patients with relapsing or refractory follicular lymphoma regardless of EZH2 mutation status.
The phase 2 study, involving 99 patients from nine countries including Australia, tested 800mg tazemetostat orally twice daily in consecutive 28-day cycles.
It found an overall response of 69% in patients with EZH2 mutation and 35% in patients with EZH2 wild type. This included complete responses of 13% and 4% in the two groups respectively.
The duration of response was 10.9 months and 13 months respectively and the median PFS was 13.8 months and 11.1 months in the two groups.
“Although this phase 2 study was not designed to compare outcomes in patients with different EZH2 mutational statuses, patients with EZH2mut follicular lymphoma had a higher objective response rate than did those with EZH2WT follicular lymphoma,” the study said.
“Despite a higher proportion of poor risk features in patients in the EZH2WT cohort, we believe that the nearly doubled objective response rate for the EZH2mut cohort was mainly driven by the EZH2 mutation.”
The study, published in The Lancet Oncology, also found in a post hoc analysis that continued treatment could deepen the level of response.
Five of six patients in the EZH2mut cohort and one of two in the EZH2WT cohort had a partial response before subsequently attaining a complete response.
“These data suggest that, with an extended dosing interval, inhibition of EZH2 not only sustains responses, but can transform partial responses into complete responses in some patients.”
And extended dosing could be supported given tazemetostat was well tolerated.
“The low prevalence of treatment-related adverse events and the low proportion of patients requiring dose reductions or discontinuing therapy due to treatment-related adverse events allowed for a longer duration on therapy.”
The investigators said that although tazemetostat monotherapy had demonstrated anti-cancer activity, the drug’s tolerability and potential immunomodulating properties also make it an attractive candidate for combination use.
“For example, tazemetostat might be able to enhance the sensitivity and immunogenicity of follicular lymphoma to lenalidomide and rituximab when given in combination. In addition, given that the PI3K signalling pathway is known to promote oncogenesis by regulating the epigenome, tazemetostat could be used in combination with PI3K inhibitors to potentially synergistically increase the anti-tumour efficacy of these two distinctly different treatments.”
A Comment article in The Lancet Oncology also said studies of combination therapies were warranted.
It suggested that in the short term, a solution would be to combine an EZH2 inhibitor with chemotherapy or immunotherapy in an attempt to increase the proportion of patients who respond.
“Undoubtedly, and as indicated by the finite duration of response, tumours will naturally find ways to bypass epigenetic inhibition, and therefore a specific targeted combination therapy approach will be needed.”
“Next steps include identifying the mechanisms of on-target resistance from secondary EZH2 mutations that prevent drug binding so that next-generation EZH2 inhibitors can be developed, and deciphering the mechanisms of off-target resistance that activate concurrent pathways (eg, PI3K/AKT/mTOR and MAPK) to identify potential combination therapies.”
The FDA granted accelerated approval to tazemetostat for follicular lymphoma in June this year.
It is also being evaluated for other indications including sarcoma and prostate cancer.